Polymer adjuvants for innate and cellular based vaccination

用于先天和细胞疫苗接种的聚合物佐剂

• 批准号: EP/H049738/1
• 负责人: Leonard Seymour
• 金额: $ 33.77万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FH049738%2F1
• 关键词: Polymer; adjuvants; innate; cellular; based

In the early days of commercial vaccine manufacture, significant variation between the effectiveness of different batches of the same vaccine were correctly ascribed to contamination of the reaction vessels. However, more scrupulous attention to cleanliness seemed to reduce the effectiveness of the vaccines, suggesting the contaminants actually enhanced immunogenicity. These contaminants were described as 'adjuvants'; agents which stimulate the immune system and increase the response to a vaccine, without having any intrinsic antigenic effect. They do this by creating a non-specific pro-inflammatory environment, where presentation of specific antigens leading to a vaccine response is much more efficient. Experience shows that adjuvants make a crucial contribution to the development of effective vaccines, and many adjuvants are now in widespread use, including oils, aluminium salts and virosomes.The field of vaccination is of ever-increasing importance, ranging from successful eradication of Smallpox in 1977 (estimated to have saved 30 m lives) through to the pressing need for prophylactic (and ideally therapeutic) vaccines for HIV, malaria, TB and cancer. New adjuvants will make an important contribution to the development of new vaccines, as some of the most effective adjuvants to date (such as Freund's adjuvants) cannot be manufactured to cGMP and are not suitable for clinical use. One way to address this shortfall is to design and produce potent and specific synthetic molecular adjuvants which are suitable for cGMP manufacture.We will synthesize polymer-TLR ligands conjugates which are capable of binding their receptor and activate a programmed cytokine response. Multivalent reactive polymers will be synthesized using controlled radical polymerization to obtain polymers which have a narrow molecular weight distribution. Hydrophilic monomers such as polyethylene glycol methacrylate, or N,(2-hydroxypropylmethacrylamide) will be co-polymerized with either an activated ester bearing monomer or an azide bearing monomer for subsequent modification. Three parameters of polymer structure will be examined in order to determine optimum capacity of the materials to induce an immune response: Firstly the molecular weight and polydispersity of the polymer; secondly the number of TLR ligands per polymer and finally the spacer length and properties. All of these parameters will be adjusted in parallel and are important in understanding how features of the material alter the immune response.Biological activity will be initially assessed using reporter cells which are activated upon stimulation of any TLR ligands. A reporter protein is expressed and reflects the level of activation of the cells and thus an indicator of stimulation. Secondly, the specific activity of the ligand-polymer conjugates will be assessed to determine whether the materials stimulate either a cell based or antibody based immune response by measuring the relative quantities of the cytokines released following activation.

在商业疫苗生产的早期，不同批次的相同疫苗的有效性之间的显著差异被正确地归因于反应容器的污染。然而，对清洁的过分关注似乎会降低疫苗的有效性，这表明污染物实际上会增强免疫原性。这些污染物被描述为“免疫剂”;刺激免疫系统并增加对疫苗的反应的试剂，而没有任何内在的抗原效应。他们通过创造一个非特异性的促炎环境来做到这一点，在这种环境中，特异性抗原的呈递导致疫苗应答的效率要高得多。经验表明，佐剂对有效疫苗的开发做出了至关重要的贡献，许多佐剂现在得到广泛使用，包括油、铝盐和病毒体。（估计已经挽救了3000万人的生命）到对艾滋病、疟疾、结核病和癌症的预防性（理想情况下是治疗性）疫苗的迫切需求。新型佐剂将对新疫苗的开发做出重要贡献，因为迄今为止一些最有效的佐剂（如弗氏佐剂）无法按照cGMP生产，不适合临床使用。解决这一不足的方法之一是设计和生产适用于cGMP生产的有效和特异性的合成分子佐剂。我们将合成能够结合其受体并激活程序化细胞因子应答的聚合物-TLR配体缀合物。多价反应性聚合物将使用受控自由基聚合来合成，以获得具有窄分子量分布的聚合物。亲水性单体如聚乙二醇甲基丙烯酸酯或N，N-（2-羟丙基甲基丙烯酰胺）将与带有活化酯的单体或带有叠氮化物的单体共聚，用于随后的改性。将检查聚合物结构的三个参数，以确定材料诱导免疫应答的最佳能力：首先是聚合物的分子量和多分散性;其次是每个聚合物的TLR配体数量，最后是间隔基长度和性质。所有这些参数将被平行调整，并且对于理解材料的特征如何改变免疫应答是重要的。生物活性将使用在任何TLR配体刺激后被激活的报告细胞进行初步评估。报告蛋白被表达并反映细胞的活化水平，因此是刺激的指标。其次，通过测量活化后释放的细胞因子的相对量，评估配体-聚合物缀合物的比活性以确定材料是否刺激基于细胞或基于抗体的免疫应答。

项目成果

Targeting of liposomes via PSGL1 for enhanced tumor accumulation.

通过 PSGL1 靶向脂质体以增强肿瘤积累。

• DOI: 10.1007/s11095-012-0875-5
• 发表时间: 2013-02
• 期刊: PHARMACEUTICAL RESEARCH
• 影响因子: 3.7
• 作者: Carlisle, Robert;Seymour, Leonard W.;Coussios, Constantin C.
• 通讯作者: Coussios, Constantin C.

Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound.

• DOI: 10.1093/jnci/djt305
• 发表时间: 2013-11-20
• 期刊: Journal of the National Cancer Institute
• 作者: Carlisle R;Choi J;Bazan-Peregrino M;Laga R;Subr V;Kostka L;Ulbrich K;Coussios CC;Seymour LW
• 通讯作者: Seymour LW